The participation of endothelin has been suggested in adult diseases which have been increasing in recent years, particularly in those which are caused by ischemia such as cerebral infarction, angina pectoris, myocardial infarction and renal insufficiency. Endothelin is a peptide comprising 21 amino acids produced by endothelial cells and endothelin-1, endothelin-2 from which endothelin-3 have been obtained. In this specification, a group comprising these endothelins will be referred to as "endothelin".
It has been reported that endothelin exhibits the most powerful and long-lasting vasoconstrictive action, hypertensive activity and potentiating action for contraction of heart muscles among the natural and synthetic substances which were known hitherto. Such actions of the peptide have been thought to be due to the endothelin receptors which are thought to be present in smooth muscle membranes of the blood vessel and others. With regard to the endothelin receptors, endothelin-A receptor and endothelin-B receptor have been known. Hereinafter, they will be referred to as "endothelin receptors".
Accordingly, compounds having affinity for endothelin receptors while showing endothelin antagonistic activity have prophylactic and therapeutic effects against diseases which are caused by ischemia such as cerebral infarction, angina pectoris, myocardial infarction, renal insufficiency and liver insufficiency and thus development of these compounds has been greatly expected. With respect to compounds having an endothelin antagonistic action prepared by means of synthesis, those which are disclosed in the EP-A-510526 and 526708 and the PCT Gazette 9308799 have been known. However, the degree of endothelin antagonistic action of these compounds has not been satisfactory.
An object of the present invention is to offer endothelin antagonists containing thienopyrimidine derivatives exhibiting an excellent endothelin antago3nistic action, novel thienopyrimidine derivatives and methods of manufacturing them.
Under the above-mentioned circumstances, the present inventors have carried out extensive investigations in order to find novel compounds which can be used as endothelin antagonists and found that the thieno[2,3-d]pyrimidine derivatives exhibit an excellent endothelin antagonistic action. As a result of further investigations based upon such a finding, the present inventors have achieved the present invention.